Risk of Self-Reported Penicillin Allergy Despite Removal of Penicillin Allergy Label

This secondary analysis of adult patients in the Penicillin Allergy Clinical Decision Rule (PALACE) Study investigates the risk of self-reported penicillin allergy despite removal of penicillin allergy label.

In brief, following informed consent, a dose of penicillin (orally) is given to patients with a 1-2 hours observation period post dose.Vital signs are monitored at baseline and as needed.Emergency medication is available on site (including adrenalin administration).

Negative oral penicillin provocation (challenge)
No antibiotic associated immune mediated reactions.

Serious adverse event
A serious adverse event will be defined as any adverse drug event/experience occurring at any dose that in the opinion of the investigators is causal for any of these outcomes: (1) death; (2) life threatening reaction; (3) inpatient hospitalization; (4) results in persistent or significant disability/incapacity; (5) congenital anomaly or birth defect; or (6) requires intervention to prevent permanent impairment or damage.

Antibiotic Associated Immune Mediated Adverse Event
Any immune mediated [immediate (IgE) or non-immediate (T-cell)] reaction within 48 hours of oral provocations judged by two independent reviewers.

Antibiotic Associated non-immune Adverse Event
An antibiotic associated adverse event will include any non-immune mediated reaction (e.g.nausea, vomiting, diarrhea etc.) within 48 hours of oral provocations judged by two independent reviewers.

Low risk penicillin allergy
Unknown > 10 years, maculopapular rash (MPE) greater than 10 years prior, Type A adverse drug reaction (ADR) as per published definition [1], local injection site reaction, childhood benign exanthema.

Delabelled
The removal of a patient's reported allergy if no adverse event is noted following direct oral provocation or challenge with implicated drug NSP Narrow spectrum penicillin including Penicillin VK, penicillin G, amoxicillin, ampicillin, flucloxacillin, dicloxacillin.

NSB
Narrow spectrum beta-lactam including the NSP + cefazolin and cephalexin.

INTRODUCTION/BACKGROUND INFORMATION
b. LAY SUMMARY Penicillin allergies are a major burden on patients and health care worldwide.Currently, up to 1 in 4 Australian patients admitted to hospital will report an antibiotic allergy, many of which limit appropriate antibiotic use and lead to poorer health outcomes.In some instances, patients will report what is considered a "low-risk" penicillin allergy and could be eligible for a penicillin challenge (i.e. a simple test dose) to determine if they are still allergic.However, the standard of care for a Penicillin allergy assessment includes skin testing (prick testing and intra-dermal testing) and, if negative, a graded oral challenge (1/10 of the dose followed by 1/1 of the dose).We have developed a penicillin allergy clinical decision rule, the PEN-FAST, that facilitates point-of-care risk assessment of patient-reported penicillin allergies.A score of less than 3 is associated with a high negative predictive value [2].A direct oral challenge will not only reduce the time spent in clinic but also the related costs and allow an increased access to the allergy clinic for the patients with a severe allergy phenotype.

c. INTRODUCTION
Penicillin allergies are highly prevalent in the health-care setting and associated with second-line inferior antibiotics being prescribed.An incorrect penicillin allergy label leads to increased risk of resistant organisms, side effects from second-line antibiotics as well as increased medical costs [3].Over 50% of reported penicillin allergies are considered low risk and can be identified and removed (i.e.de-labelled) via point-of-care single test dose provocation (i.e.challenge).However, the safety and efficacy of antibiotic allergy assessment, such as PEN-FAST, followed by direct oral penicillin provocation based on this validated clinical tool's score is unknown.
This study aims to compare skin testing followed by oral drug challenge, if negative, in the outpatient allergy clinic to a direct oral penicillin provocation (i.e.test dose) when the PEN-FAST score is less than 3.
Our previous work has shown that more than 85% of penicillin allergies can be removed by formal skin prick allergy testing [9], and 96-98% with low-risk allergies can be removed by point-of-care oral provocation [10].Our group has internally and externally validated a novel penicillin allergy clinician decision rule (PEN-FAST) that is able to identify low risk penicillin allergies with a negative predictive value of 96% (95% CI 94-98%) [2].The only currently available prospective randomized controlled trial evaluated the safety of drug challenge in a low-risk penicillin allergy patient group [3].Specifically, the authors compared skin testing followed by drug challenge (if skin testing negative) versus direct challenge and showed that the direct challenge was a safe and effective alternative for delabeling penicillin allergy.In our international cohort, we will use the validated clinical tool, PEN-FAST, to determine if a score of less than 3 is as safe and effective as standard of care defined as skin testing followed by drug challenge if negative.
Therefore, whilst validated tools exist to enable inpatient penicillin assessment and de-labelling, limited evidence is available regarding the safety and efficacy in the outpatient clinic.The ability to deliver point-of-care penicillin allergy testing for a large cohort of patients, without skin testing, will improve patient access to testing and utilization of preferred penicillin antibiotics.

STUDY OBJECTIVES
e. HYPOTHESIS Using the PEN-FAST tool in an outpatient clinic setting leads to safer and faster assessments in Penicillin Allergic patients compared to standard of care (skin testing followed by oral provocation if negative).
f. STUDY AIMS Evaluate the non-inferiority of using PEN-FAST score guided management compared to standard care (skin testing followed by oral provocation if negative).Eligible patients referred to the outpatient clinic reporting a penicillin allergy will be identified and assessed with a standard clinical history and the calculation of the PEN-FAST score (Figure 2 and Appendix 2).PEN-FAST is a three-point clinical assessment tool recently externally validated in a multicenter study, with a PEN-FAST score of < 3 associated with 96.7% negative predictive value [2].We will include 380 patients and allocate them 1:1 ratio to the intervention group (PEN-FAST tool followed by oral penicillin provocation if score is less than 3) and control group (standard of care).

g. OUTCOME MEASURES
Only the patients with a score less than 3 will be randomized 1:1 following informed written consent to the intervention arm (direct oral penicillin challenge) or standard of care (skin testing following by oral challenge if negative).

Study population: Adult patients ≥ 18 years reporting a penicillin allergy
Primary objective: The difference in the proportion of patients with a positive oral provocation (i.e.immune-mediated reaction)

Pre-randomisation questionnaire:
Prior to the intervention or standard of care procedures, participants will be asked to complete a Drug Hypersensitivity Pre-Questionnaire (Appendix 3).

Intervention:
The patient will receive a single dose of oral penicillin, following baseline vital signs (i.e.temperature, heart rate, blood pressure, respiratory rate, skin check).If the patient reports a reaction to either penicillin unspecified, penicillin G, penicillin V, semi-synthetic anti-staphylococcal penicillins, ampicillin, amoxicillin or amoxicillin/clavulanate, he/she will be administered either the implicated drug or amoxicillin, consistent with site local practice.The dose used for amoxicillin is 250 mg or the lowest available dose according to center availability.The implicated drug should also be administered at the lowest available dose.For the amoxicillin/clavulanate allergic patients, they will retain an allergy label to clavulanate.
Nursing staff will repeat vital signs as needed after oral challenge while observing for signs of an immune mediated adverse reaction.If at any stage an antibiotic associated adverse event is noted, standard of care treatment is offered by the attending clinician (ex.adrenalin for immediate hypersensitivity reaction).

Control:
Routine management as per the treating clinicians that include skin prick and intradermal beta-lactam testing, followed by oral penicillin challenge in the setting of negative skin testing.
There will be no additional blood sampling or testing for patients in either arm of the trial.Patients in both groups will be able to directly contact a member of the clinical team (phone or email) if any serious or antibiotic associated adverse events occurs in the next 24 to 48 hours.Depending on the drug j.RANDOMIZATION Permuted block design randomisation will be used, stratified by the hospital site.

Follow-up Telephone
Randomization will be performed via RedCap just prior to the intervention.The allocation sequence will be concealed until the time of the randomisation.k.STUDY METHODOLOGY All eligible patients who have a history of penicillin allergy will be evaluated using PEN-FAST tool and those with PEN-FAST score <3 will be randomized to either:

OR
Standard of care (skin testing followed by oral drug challenge if negative)

STUDY POPULATION
l. RECRUITMENT PROCEDURE All adult patients referred to the outpatient clinic that have a documented or reported penicillin allergy will be screened for eligibility.Because of this risk, the direct oral challenge is done in an outpatient hospital setting with surveillance from the medical staff (doctors and nurses).All the outpatient clinics are equipped with anaphylaxis managements kits and have access to resuscitation equipment as needed.Patients are supervised in the clinic for minimum one hour after the challenge.
An independent data safety management board (DSMB) will be established to review the progress of the study and monitor adherence to the protocol, participant recruitment, outcomes, complications, and other issues related to participant safety.They will also monitor the assumptions underlying sample size calculations for the study and alert the investigators if an increased recruitment effort is required.The DSMB will make recommendations as to whether the study should continue or be terminated, consider participant safety or other circumstances as grounds for early termination, including either compelling internal or external evidence of treatment differences or feasibility of addressing the study hypotheses (e.g.poor participant enrolment).
q. HANDLING OF WITHDRAWALS Participants may withdraw from the study at any point.In these circumstances, the participant's data collected before the withdrawal might be included in the analysis.

r. REPLACEMENTS
No withdrawals post randomization will be replaced.

s. SAMPLE SIZE ESTIMATION & JUSTIFICATION
The null hypothesis is that the difference in the proportion of positive allergy tests is not larger than 5 % (non-inferiority margin).To achieve 80% power assuming the event rate in control group being 4% and type 1 error probability of 5 % (one-sided), a total of 380 patients need to be randomized (190 per group).

t. STATISTICAL METHODS TO BE UNDERTAKEN
Results will be presented according to CONSORT guidelines.Analysis will be on intentionto-treat principle with additional per-protocol analysis.Descriptive statistics for patient characteristics, penicillin allergy history and the reasons patients did not undergo penicillin allergy assessment will be presented.Continuous variables will be presented as median (interquartile range) and categorical variables as frequency (percentage).
Primary result will be presented as the absolute difference of the primary outcome between groups with 90% confidence interval (due to one-sided 5% significance used in sample calculation).If the upper level of this interval is greater than non-inferiority margin (5%), the null hypothesis cannot be rejected.All other secondary outcomes will be presented as difference in the proportion with 95% CI and OR with 95 % CI.Continuous outcomes will be compared using t-test or rank sum test (depending on the distribution).All analyses will be conducted using STATA v16.The collected data from every institution will then be stored on an electronic database (i.e.REDcap Austin Health) on password-protected computers.Paper data and study related documents used in this study will be re-identified and only a master log will be maintained to identify participants and their study data.The log will be locked in a protected office.All data for study will be retained for a period of fifteen years after which all electronic and paper data will be destroyed in accordance with hospital policy in place at the time.If the combination of these routinely collected data and information derived from this study provides useful clinical insights into the management of penicillin allergy, we plan to publish our findings.Authorship will be determined by the Investigational team with reference to the International Committee of Medical Journal Editors guidelines.Only aggregated non-identifiable patient data will be presented or published.
w. CONFIDENTIALITY AND SECURITY An independent data safety management board (DSMB) will be established to review the progress of the study and monitor adherence to the protocol, participant recruitment, outcomes, complications, and other issues related to participant safety.
x. ANCILLARY DATA   "Hello could I please speak to (patient's full given name and surname)?"Hello, I am ________, (name and function in the hospital).You have participated in a study on Penicillin allergy, the PALACE Study, about 6 months ago.We are now contacting for the second part of the study in order to find out what antibiotics you have used after antibiotic allergy testing at our center (Name the center).You have been selected to be involved in this project because you came to our center and had your antibiotic allergy reviewed.
Before we proceed further, can I please confirm your full name and date of birth?
If you agree to continue to participate in this study, we will ask you some questions about your allergies and what antibiotics you have taken and any problems with your antibiotics recently.Usually the interview takes about 10 minutes, but if we identify some problems with your allergies and we help you to solve these problems, it might take longer.If we identify some problems, we might ask for your permission to contact your local doctor or the antibiotic allergy service at our center that can help you to solve these problems.Taking part in this interview is completely voluntary and will not affect your future care at our center.

Questionnaire: A 6 -FIGURE 1 -Figure 2 -
FIGURE 1 -OVERVIEW OF THE STUDY DESIGN

Study
Name: PALACE Study Protocol Number: PALACE Version & date: Version 4, dated 09-03-2021 Page 15 of 24 more than one body system.Symptoms such as hives, swelling and trouble breathing usually begin within 5 -30 minutes of exposure to an allergen and may lead to anaphylactic shock which can be fatal if not treated immediately.Serious reactions such as anaphylaxis have not been reported with this test dose procedure but are theoretically possible.Other side effects such as itch, nausea, vomiting, diarrhea, abnormalities of liver or kidney tests are also possible, although very unlikely.
OF WHERE RECORDS WILL BE KEPT & HOW LONG WILL THEY BE STORED Patient clinical details and demographics will be recorded on data collections forms usually used in the outpatient clinic at each participating center.Completed forms will be kept in the Department of Infectious Diseases at the Austin hospital, Peter MacCallum Cancer Center, Royal Melbourne Hospital and the Allergy-Immunology departments at the CHUM, MUHC and Vanderbilt University Medical Center.
Telephone survey scriptVerbal consent script for patients who were randomized in the trial.
If the patient is not at home: "Is there a time that I could call back to speak with (patient's name)?"If the patient is busy: "Is there another time that I could call back that would be convenient?"Patient questions Do you consent for us to check what antibiotics you have been prescribed by your doctors in the community and dispensed by your pharmacy?We can check this via a program called (name the local program depending on the center).1. Do you remember having a test dose of penicillin in the outpatient clinic?a.If Yes, please tell me whether you agree with these statements: i. "I felt safe during the test dose.disagreeii."I recommend the penicillin assessment to other patients with a penicillin allergy." 1. Strongly agree 2. Agree 3. Neutral Study Name: PALACE Study Protocol Number: PALACE Version & date: Version 4, dated 09-03-2021 Page 23 of 24

TABLE OF CONTENTS CONTENTS Table of Contents
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of 24 definition An
independent data safety management board (DSMB) will be established to review the progress of the study and monitor adherence to the protocol, participant recruitment, outcomes, complications, and other issues related to participant safety.

24 12. APPENDIX 2 -PEN-FAST CLINICAL DECISION RULE PALACE Study
The use of penicillin allergy clinical decision rule to enable direct oral penicillin provocation - Study Name: PALACE Study Protocol Number: PALACE Version & date: Version 4, dated 09-03-2021 Page 20 of 24 13.

following questions concern the influence your drug allergy has on your quality of life. Answer every question by marking the appropriate box with an x. You may choose from one of the following answers.
Study Name: PALACE Study Protocol Number: PALACE Version & date: Version 4, dated 09-03-2021 Page 21 of 24 Study Name: PALACE Study Protocol Number: PALACE Version & date: Version 4, dated 09-03-2021 Page 22 of 24